The biological effect and the mode of action of the CXCL7-CXCL12 chemokine heterodimer

摘要 趋化因子在健康和疾病中是必不可少的，如感染、自身免疫性疾病、动脉粥样硬化 艾滋病毒/艾滋病和癌症。许多趋化因子相互参与异嗜性相互作用以形成 杂二聚体，导致协同活性增强或降低取决于杂二聚体的性质- 形成趋化因子。趋化因子异二聚体的作用机制尚不清楚。此前，我们 确定了所有与两种最丰富的血小板趋化因子CXCL4相互作用的血小板源性趋化因子 和CXCL7。CXCL12趋化因子与CXCL7表现出强烈的异二聚化作用。在当前 项目，我们将确定这些新的相互作用的生物学后果以及 CXCL7-CXCL12杂二聚体。在目标1中，我们将确定CXCL7-CXCL12异二聚化对 CXCL12介导的CXCL7-CXCL12异二聚体结合激活CXCL12‘S受体的活性 CXCR4，以及基于CXCL12的异源二聚体对细胞作用的分子机制 迁移。在目标2中，我们将确定CXCL7-CXCL12异二聚化对CXCL7介导的 CXCL7-CXCL12中性粒细胞黏附和迁移活性及其与CXCR2受体的关系 异源二聚体介导的活性。这个项目的结果将加深我们对趋化因子生物学的理解 并为开发异嗜性趋化因子的新型治疗干预策略的未来发展提供了信息 互动。

ABSTRACT Chemokines are essential in health and disease such as infections, autoimmune diseases, atherosclerosis, HIV/AIDS, and cancer. Many chemokines engage in heterophilic interactions with each other to form heterodimers, leading to synergistic activity enhancement or reduction dependent on the nature of heterodimer- forming chemokines. The mode of action of chemokine heterodimers remains poorly understood. Previously, we identified all platelet-derived chemokines interacting with the two most abundant platelet chemokines, CXCL4 and CXCL7. The CXCL12 chemokine demonstrated strong heterodimerization with CXCL7. In the current project, we will determine the biological consequences of these new interactions and the mode of action of the CXCL7-CXCL12 heterodimer. In aim 1, we will determine the effect of CXCL7-CXCL12 heterodimerization on CXCL12-mediated activities, that the CXCL7-CXCL12 heterodimer binds and activates the CXCL12’s receptor CXCR4, and the molecular mechanism underlying the effect of the CXCL12-based heterodimers on cell migration. In aim 2, we will determine the effect of CXCL7-CXCL12 heterodimerization on CXCL7-mediated activities (neutrophil adhesion and migration) and the involvement of the CXCR2 receptor in CXCL7-CXCL12 heterodimer-mediated activities. The results of this project will deepen our understanding of chemokine biology and inform the future development of novel therapeutic intervention strategies exploiting heterophilic chemokine interactions.